Soliva and Speiser [Pharmaceutica Acta Helvetivae, 41, 176 to 191 (1966)] discussed the general and biokinetic aspects of peroral depot medication and followed theoretical considerations to the conclusion that, in the case of an ideal depot-form of medicament, the release of active substance should occur at a constant rate, i.e. in accord with a reaction of zero order.
To solve the problem, Lehmann and Dreher [Pharm. Ind., 31, 319 to 322 and 409 to 412 (1969)] proposed the production of tablets with a porous matrix, which were to be provided with a thin permeable Eudragit retard lacquer coating*. The method suffers, however, from the disadvantage that the release of active substance depends on the viscosity of the matrix, on the quantity of matrix, on the specific surface area of the tablets, on the pressing pressure and on the quantity of Eudragit. Dependence on so many factors makes production of such tablets (with a constant active-substance-release rate) a complicated problem. Furthermore, release of active substance does not remain constant if the matrix tablets are subjected to a mechanical load, such as that which occurs in the gastrointestinal tract.
Lehmann [Pharma International (1971), No. 3, 34 to 41] suggested adapting the permeability of employed coating materials to suit the solubility properties of the active substances involved. In accordance with this suggestion and by using a combination of insoluble Eudragit retard with types of Eudragit* soluble in the gut, it is possible to vary the permeability of a coating for medicament, which comprises a weakly basic active substance, in accordance with the milieu, i.e. the permeability of the coating increases at that instant in which the coated medicament enters the gut and the solubility of the active substance decreases. The proposal, however, has the disadvantage that the release of active substance cannot be precisely controlled over wide ranges, since (in the case of higher amounts of Eudragit lacquers soluble in the small intestine) the dialysis membrane formed of insoluble Eudragit retard lacquer decomposes. Thus mixing ratios of over 60% by weight of soluble Eudragit lacquer and under 40% by weight of insoluble Eudragit retard lacquer do not lead to any satisfactory results. For example a dialysis membrane made up of 50% by weight of Eudragit retard and 50% by weight of Eudragit soluble in the small intestine completely decomposes at a pH-value of 6 to 7 after 4 hours at the most. Increasing the amount of material soluble in the small intestine to 60% by weight results in a dialysis membrane which decomposes within one hour in artificial intestine juice having a pH-value of 7.3. FNT These polymeric lacquer substances, based on an acrylate and on a methacrylate, respectively, are described in "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and augrluzlude Gebiete" [Editio Cantor KG] by H. P. Fiedler on pages 202 and 203 and in the "Eudragit" brochure of Messrs. Rohm and Haas (1967).
German patent specification (Offenlegungsschrift) No. 2,010,416 (corresponding to U.S. Pat. No. 3,835,221) suggests the production of an oral form of medicament with a retarding action in which the active material is applied to indifferent vehicle balls or spherulets which are then coated with a resorption delaying coating of polyvinyl acetate, preferably in admixture with ethylcellulose. The polyvinyl acetate used has a k-value [determined in accordance with the method of Fikentscher, Cellulose, 13, 18 (1932)] of from 20 to 40, and the ethylcellulose used has an ethoxyl content of from 44 to 49.9 at a viscosity between 7 to 100 cp. Such method, however, is limited to active substances which are equally soluble throughout the entire digestive tract.
German patent specification (Offenlegungsschrift) No. 2,148,391 describes a mixture of approximately 90% by weight of cellulose acetate-phthalate and approximately 10% by weight of ethylcellulose, inter alia, as a binding agent (for particles, pressed to form tablets, of 150 microns in diameter) and a calcium or magnesium salt of a higher fatty acid as a barrier agent. The barrier agent delays the penetration of liquids into the interior of the tablets and thus prevents release of the active substance. A drawback of this method, however, is that release of the active substance is only very approximately linear (see example 3 of the noted German patent specification). Furthermore, the use of the barrier agents does not provide for any exact control of the release of the active substance based on the pH-value.
German patent specifications (Patentschriften) Nos. 1,467,781 and 1,467,786 describe dragees with a retarded release of medicament. These dragees consist of pressed pulps containing from 50 to 500% by weight of a swelling agent and from 10 to 50% by weight of a water-insoluble polyvinyl-acetate or a film-forming cellulose acetate-phthalate, the content of swelling agent and of polymers being fixed in relation to the active constituent of the pulp. Illustrative of the swelling agents mentioned are cellulose ethers, such as carboxymethylcellulose, oxyethylcellulose and methyl-cellulose.
A disadvantage of this retard form is that the active drug constituent is not released with constant speed in either artificial digestive fluids or in the gastrointestinal tract. This can readily be seen from example 3 of the '781 patent, which shows the considerable tolerances of the release rate. When the medicament is, e.g., a dragee, it will be intact in the stomach at one instant, but whether the dragee will remain in the stomach or leave it during the next emptying of the stomach is uncertain. Therefore medicament release depends on factors which are hard to control. A further disadvantage is that medicament release within specified tolerances is only achieved with a very large portion of auxiliary substances.
The swelling cellulose ethers used are high-molecular-weight substances which have a viscosity of about 1000 centipoises (cp) (cf. examples 1 to 4 of German specification '781 and examples of German specification '786) and swell in water to form a gel.